GSTT1 Gene Deletion Research Articles

Association between GSTT-1 gene deletion and the susceptibility to oral squamous cell carcinoma in cigarette-smoking subjects

Oral squamous cell carcinoma (OSCC) is related to tobacco use and alcohol consumption and the individual susceptibility for development of this tumor has been associated with xenobiotic-metabolizing enzymes polymorphisms. Glutathione S-transferase Theta-1 (GSTT1) is a phase II metabolic enzyme that catalyzes detoxification reactions of carcinogenic compounds. A genetic polymorphism of the GSTT1 gene is characterized by a complete gene deletion and consequent absence of the enzyme. The null genotype (gene deleted) of GSTT1 has a decreased capacity in detoxifying carcinogens present in tobacco smoke, leading the formation of DNA-adducts and DNA damage. The purpose of the present study was to evaluate the association between GSTT1 polymorphism and risk for OSCC development in a Brazilian population. We investigated the GSTT1 polymorphism in 87 patients with OSCC and 81 age-sex matched controls. The genotypes were studied by PCR-based methods. Individuals homozygous for the wild type GSTT1 (+/+) and heterozygous (+/0) were grouped together. The prevalence of GSTT1 deficiency (null) was significantly higher in the group with OSSC patients with oral cancer of the floor of the mouth. The results suggest that GSTT1 polymorphism increases the risk for OSCC development.

Polymorphism within the glutathione S-transferase P1 gene is associated with increased susceptibility to childhood malignant diseases.

Glutathione S-transferases (GSTs) are involved in the metabolism of carcinogens and anticancer drugs. Functional polymorphisms exist in at least three genes that code for the GSTs, such as the GSTM1 and GSTT1 gene deletions or the A-G transition within the GSTP1 gene, which represents distinct GSTP1a and GSTP1b alleles. In the present case-control study, we aimed at estimation of the relationship between the GSTM1, GSTT1, and GSTP1 genotypes and the susceptibility to various types of childhood malignancies and the early relapses of diseases. Using the polymerase chain reaction on the DNA extracted from peripheral blood leukocytes, we identified the GSTM1, GSTT1, and GSTP1 genotypes in 234 children at the initial stage of a childhood malignancy as well as in 460 age-and sex-matched healthy subjects who served as controls. The follow-up period for the effects of the anticancer therapy ranged from 11 to 43 months. Compared to the controls, a significant increase in the frequency of the GSTP1b/GSTP1b genotype (odds ratio (OR) 5.7; 95% confidence limit (CL) from 2.4 to 13.8; Pearsons Chi-square P = 0.0001) was detected in the children with neoplasms. The GSTM1 and GSTT1 genotypes did not show any correlation with the risk of the de novo diagnosed neoplasms. During the observation, 62 children (26%) were found to be present with a local or disseminated recurrence of the diseases. The analysis indicated a trend in increasing risk of relapse for carriers of the GSTP1a allele (OR = 3.29; 95% CL from 0.73 to 14.67 P = 0.03). Our results support the hypothesis that GST genotype affects etiology and outcome of a variety of childhood malignancies.

GSTT1 gene deletion is associated with lung cancer in Mexican patients.

Glutathione S-transferase (GST) is a dimeric detoxifying isoenzyme, involved in the deactivation of carcinogens, several tobacco-derived carcinogens, and xenobiotics. It catalyzes the reduction of glutathione to its thioester; thus, deficiency in GST activity due to homozygous deletion of the GSTT1 gene (null genotype) may play a role in the induction of lung cancer by smoking.We studied the distribution of GSTT1 gene deletion in peripheral blood DNA samples from 178 healthy controls (41 nonsmokers, 63 passive smokers and 74 smokers) and 52 lung cancer patients. Comparisons between groups showed that there was an increased lung cancer risk for individuals with the GSTT1 null genotype. Cancer patients showed significant differences when compared with controls: nonsmokers, passive smokers, and smokers. Twenty-one percent of lung cancer patients carried the deletion versus 2% among nonsmokers not exposed to passive smoking, 6% among passive smokers, and 5% among smokers. Thus, there is a significant association between this genotype and the possibility to risk of developing lung cancer.

Occupational exposure to styrene: modulation of cytogenetic damage and levels of urinary metabolites of styrene by polymorphisms in genes CYP2E1, EPHX1, GSTM1, GSTT1 and GSTP1.

Styrene is widely used in the production of various plastics, synthetic rubber and resins. The aim of this study was to evaluate if individual polymorphisms in xenobiotic metabolizing enzymes, related with the metabolic fate of styrene, could modify individual susceptibility to the possible genotoxic effects of the styrene exposure. Twenty-eight reinforced plastic workers and 28 control subjects were studied. In the selected population the urinary styrene metabolites mandelic (MA) and phenylglyoxylic (PGA) acids were quantified, sister chromatid exchanges (SCE) and micronuclei (MN) were assessed in peripheral lymphocytes and all the subjects were genotyped for GSTM1, GSTT1 (gene deletions), GSTP1 (codon 105 ile==>val), EPHX1 (codons 113 tyr==>his and 139 his==>arg) and CYP2E1 (DraI polymorphism in intron 6). The results obtained showed a significant difference between the levels of SCE, but not in MN levels, in exposed workers as compared with the control group. The GSTP1 and CYP2E1 individual genotypes modulate the baseline levels of SCE that are lower in non-wild type individuals for both polymorphisms. The GSTM1 null individuals with low levels of exposure have significantly higher urinary levels of MA+PGA. The present data seem to suggest that apart from the methodology usually used for monitoring populations occupationally exposed to styrene (urinary metabolites and biomarkers of early biological effects) the analysis of individual genotypes associated with the metabolic fate of styrene should also be carried out in order to evaluate the individual genetic susceptibility of exposed populations.

Increased frequencies of glutathione S-transferase(GSTM1 and GSTT1) gene deletions in Korean patients with acquired aplastic anemia

AbstractPatients with reduced ability to metabolize environmental carcinogens or toxins may be at risk of developing aplastic anemia. Glutathione S-transferase (GST) has been implicated in detoxifying mutagenic electrophilic compounds. This study asked whether the homozygous gene deletions of GSTM1 andGSTT1 affect the likelihood of developing aplastic anemia. The incidence of GSTM1 and GSTT1 gene deletions was significantly higher for aplastic anemia patients (odds ratio [OR]: 3.1, P = .01 and OR: 3.1,P = .004, respectively) than for healthy controls. Among the aplastic anemia patients, 17.5% (10:57) had chromosomal abnormalities at the time of diagnosis, and all aplastic anemia patients with chromosomal abnormalities showedGSTT1 gene deletions (P = .048). Individuals with GSTM1 and GSTT1 gene deletions may have greater susceptibility to aplastic anemia. It is possible that genetic instability or chromosomal damage due to abnormal detoxification of environmental toxins might have worked as an important pathophysiologic mechanism of aplastic anemia for patients with GSTT1 gene deletions.

Genetic deletions of glutathione-S-transferase as a risk factor in squamous cell carcinoma of the larynx: A preliminary report

Purpose: To test whether genetic deletions of glutathione-S-transferase (GST) are associated with squamous cell carcinoma (SCC) of the larynx. GST are a group of detoxifying enzymes that may help reduce the risk of developing cancer in response to environmental carcinogens. Polycyclic aromatic hydrocarbons, found in high concentration in cigarette smoke, are known carcinogens especially for SCC of the larynx. Individuals with absolute or relative deficiency of the GST enzyme system may therefore be at a higher risk of developing laryngeal carcinoma. Materials and Methods: Genotyping for GST-M1 and GST-T1 was performed using polymerase chain reaction (PCR) assay on fresh frozen tissue specimens of 20 patients with SCC of the larynx and on 20 control subjects with a similar smoking history. Because this assay results in the absence of a PCR product in individuals expressing the GST-M1/GST-T1 null genotype, oligonucleotide primers that amplify a portion of the albumin gene were included in a multiplex PCR as a positive control for DNA quality and PCR conditions. The chi-square test was used for statistical analysis. Results: GST-M1 gene was deleted in 80% of patients with laryngeal SCC and in 50% of control subjects (P <.05). No statistically significant difference was observed in the incidence of GST-T1 gene deletion in patients with SCC of the larynx and control subjects. Conclusion: GST-M1 gene deletion was significantly associated with SCC of the larynx and may produce a risk for this particular disease. (Am J Otolaryngol 2001;22:121-123. Copyright © 2001 by W.B. Saunders Company)

Glutathione S-Transferase M1 and T1 Gene Polymorphism in Patients with Lung Cancer Among Turkish Population

ABSTRACTSeveral polymorphic genes including those encoding for glutathione S-transferases (GSTs) have been reported to be associated with development of specific cancers. Individual variations in the expression of these enzymes have been extensively studied. In this study, the implication of two GST genes (GSTM1 and GSTT1) in the development of different types of lung cancer was investigated in Turkish patients (N=44). Our results show a 72.3% allele frequency for null GSTM1 gene among lung cancer patients and for healthy individuals (N=100) it was found to be 34%. The GSTM1 null genotype is slightly over represented in lung cancer patients (OR=0.73; CI=0.33–1.59) but did not reach a statistical importance. The frequency of deleted GSTT1 allele was 19% in normal controls that is consistent with the previous results for Caucasians. GSTT1 null genotype frequency among lung cancer patients (20.5%) was very Close to the control group (OR=0.91, CI=0.38–2.21). In all lung cancer cases 13.6 % of the patients showed homozygous deletion of both GSTM1 and GSTT1 gene and in control group 10% of the individuals had both deletion (p=0.08) suggesting that null GSTM1 and GSTT1 genotypes do not interact to potentiate the risk of lung cancers in Turkish patients.